Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing.

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.

Resultado a largo plazo de una serie de fetos con agenesia aislada del septum pellucidum / Long-term postnatal outcome of fetuses with isolated agenesis of the septum pellucidum

Objetivo: Reportar el resultado a largo plazo de una serie de fetos con agenesia del septum pellucidum aislada (ASP), con medición de su quiasma óptico mediante neurosonografía fetal (NSG). Método: Se incluyeron todas las pacientes con ASP y NSG evaluadas desde el año 2008 a la fecha y con seguimiento hasta su edad escolar. En todos los casos se consignaron los datos clínicos de NSG y de resonancia magnética (RM), cuando esta se realizó. Se entrevistó telefónicamente a los padres. Resultados: Nueve pacientes cumplieron los criterios: cuatro con displasia septo-óptica (DSO) (rango de seguimiento: 5-14 años) y cinco sin DSO (rango de seguimiento: 7-10 años). Un décimo caso se excluyó por tener solo 6 meses de seguimiento. Ninguna de las ASP tuvo otra anomalía detectada en su seguimiento. Ninguno de los casos con DSO tuvo alteración del tamaño de su quiasma óptico en la NSG ni anormalidad en la vía óptica en la RM. Conclusiones: En nuestra población, el riesgo residual de DSO frente a ASP es del 44,4%. En el seguimiento, nuestra definición de ASP por NSG no tuvo falsos negativos con relación a otras anomalías de aparición posnatal, a excepción de la DSO.

Objective: To report the long-term outcome of a series of fetuses with isolated septum pellucidum agenesis (ASP) with measurement of their optic chiasm by fetal neurosonography (NSG). Method: All patients with ASP and NSG evaluated from 2008 to date and with follow-up until their school age were included. In all cases, clinical, NSG and magnetic resonance imaging (MRI) data were recorded. Parents were interviewed by telephone. Results: Nine patients met the criteria: four with septo-optic dysplasia (SOD) (follow-up range: 5-14 years) and five without SOD (follow-up range: 7-10 years). A tenth case was excluded because only 6 months of follow-up. None of the ASP cases had another anomaly detected in their follow-up. None of the cases with DSO had anomaly of the size of their optic chiasm on NSG or abnormality in the optical pathway in the MRI. Conclusions: In our population, the residual risk of DSO versus ASP is 44.4%. At follow-up, our NSG definition of ASP had no false negatives in relation to other postnatal-onset anomalies, except for SOD.

Neurodevelopmental impairments in children with septo-optic dysplasia spectrum conditions: a systematic review.

BACKGROUND: Septo-optic dysplasia (SOD) is a rare condition diagnosed in children with two or more of the following: hypopituitarism, midline brain abnormalities, and optic nerve hypoplasia. Children with SOD experience varied visual impairment and endocrine dysfunction. Autistic-like behaviours have been reported; however, their nature and prevalence remain to be fully understood. The present systematic review aimed to explore the type and prevalence of neurodevelopmental impairments in children with SOD spectrum conditions. METHODS: The search was conducted in PubMed, EMBASE, and PsycInfo. Hand-searching reference lists of included studies was conducted. All peer-reviewed, observational studies assessing behavioural and cognitive impairments or autism spectrum disorder (ASD) symptoms in children (< 18 years) with SOD, optic nerve hypoplasia, and SOD-plus were included. Studies were excluded if they did not report standardised measures of neurodevelopmental impairments or ASD outcomes. RESULTS: From 2132 screened articles, 20 articles reporting data from a total of 479 children were included in prevalence estimates. Of 14 studies assessing cognitive-developmental outcomes, 175 of 336 (52%) children presented with intellectual disability or developmental delay. A diagnosis of ASD or clinical level of symptoms was observed in 65 of 187 (35%) children across five studies. Only five studies assessed for dysfunction across behavioural, emotional, or social domains and reported impairments in 88 of 184 (48%) of children assessed. LIMITATIONS: Importantly, high heterogeneity among the samples in relation to their neuroanatomical, endocrine, and optic nerve involvement meant that it was not possible to statistically assess the relative contribution of these confounding factors to the specific neurodevelopmental phenotype. This was further limited by the variation in study designs and behavioural assessments used across the included studies, which may have increased the risk of information bias. CONCLUSIONS: This systematic review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be high. Clinicians should therefore consider including formal assessments of ASD symptoms and neurodevelopmental impairments alongside routine care. There is, additionally, a need for further research to define and validate a standardised battery of tools that accurately identify neurodevelopmental impairments in SOD spectrum conditions, and for research to identify the likely causal mechanisms.

Role of Fetal Magnetic Resonance Imaging in Differentiating Isolated Septal Agenesis from Septo-Optic Dysplasia: Case Study and Review.

INTRODUCTION: The detection of absent septi pellucidi (ASP) during obstetric ultrasound is a rare event. However, the clinical implications of this finding are significant. ASP can be associated with severe central nervous system anomalies such as holoprosencephaly, agenesis/dysgenesis of the corpus callosum, schizencephaly, severe ventriculomegaly, and open neural tube defects. In such cases, the prognosis is poor. When no such anomalies are identified, isolated ASP usually carries a good prognosis. However, some fetuses thought to have isolated ASP actually have septo-optic dysplasia (SOD), which is associated with optic nerve hypoplasia, hypothalamic-pituitary dysfunction, and developmental delay. CASE PRESENTATION: A case in which fetal 3.0 Tesla magnetic resonance imaging (MRI) was considered crucial to definitively diagnose isolated ASP is presented. A review of the literature was conducted and analyzed to determine the role of MRI in the evaluation of fetuses with ASP, with special consideration on the differential diagnosis between isolated ASP and SOD. CONCLUSION: Differentiating isolated ASP from SOD is imperative for adequate prenatal counseling. Unfortunately, making a prenatal diagnosis of SOD requires visualization and evaluation of the fetal optic nerves, chiasm, and pituitary gland, which is very demanding and not always possible using ultrasound. Fetal MRI has the potential of obtaining high-quality images of the fetal brain, and therefore this technique can be used for establishing the differential diagnosis in utero.

Patients with septo-optic dysplasia: General ophthalmologic assessment and retinal imaging.

BACKGROUND: To evaluate the functional development and, retinal and optic disc morphology using OCT in patients with septo-optic dysplasia (SOD). METHODS: This retrospective case series included patients diagnosed with SOD between 2007 and 2020. Ophthalmologic assessment included visual acuity (VA) and funduscopy at the initial and last presentation. Retinal imaging included OCT of the macula analyzing the retinal morphology, central retinal thickness volume (CRT) and ganglion cell layer (GCL). Also, scans of the optic nerve head were taken to evaluate the retinal nerve fiber layer (RNFL) and global value. RESULTS: 38 eyes of 19 children with a mean age 6.3 ± 5.3 years were included. 31.6% showed all 3 characteristics of SOD, whereof ONH, midline defects and endocrine dysfunctions were found in 94.7%, 89.5% and 47.4% respectively. The mean VA was 0.70 ± 0.66logMar in the right eye (RE) and 0.40 ± 0.55logMar in the left eye (LE) at the initial presentation. No change of vision (RE: 0.69 ± 0.71logMar; LE: 0.31 ± 0.57logMar) was found after a follow-up period of 6.3 ± 4.5years. Funduscopy showed an ONH in 79% (n = 30/38), tortuous retinal vessels in 36.8% (n = 14/38) and a double-ring sign in 15.8% (n = 6/38). Retinal imaging showed variable morphology. 6 eyes of 4 patients showed temporal retinal thinning with corresponding GCL attenuation. The optic nerve head appearance varied between no changes, sectoral and hemispherical reduction. CONCLUSIONS: Patients suffering from SOD show diverse expression of retinal changes such as retinal, GCL and RNFL thinning in OCT. Furthermore, visual function remained stable during follow-up examinations, indicating no further alteration due to underlying pathology.

Growth hormone deficiency in a case of septo-optic-dysplasia due to SOX2 mutation: should we re-test patients during the transition period?

Gene mutations encoding transcription factors, including SOX2, have been associated with growth hormone deficiency (GHD) and abnormal pituitary development. Guidelines on GHD management in the transition period state that patients with genetic-based childhood-onset GHD can skip retesting due to a high likelihood of permanent GHD. We describe a case of septo-optic-dysplasia due to SOX2 mutation characterised by childhood-onset GHD, which showed a normal somatotropic function at the transition period. This case raises the opportunity to retest for GHD during the transition period, even in patients with a known genetic cause, in order to avoid inappropriate GH treatment.

Delineating septo-optic dysplasia.

BACKGROUND: Septo-optic dysplasia (SOD), once a variable triad of septum pellucidum defects (SPDs), optic nerve hypoplasia (ONH), and hypopituitarism, has had multiple findings added, with uncertain causes, definitions, and limits. METHOD: Literature review. RESULTS: SOD is a complex vascular sequence with confounders. CONCLUSIONS: Proximal anterior cerebral artery trunk disruptions cause overlapping primary effects, giving ONH alone most often, and isolated SPD less. ONH disruptions can spread to pituitary, SPD disruptions to the cerebral cortex, causing schizencephaly and related anomalies. Pituitary defects are rare without ONH, and cortical findings are rare without SPD. Extensions are unidirectional, so isolated pituitary or cortical defects are separate from SOD. Micro- an- ophthalmia, a suggested ONH variant, is not part of SOD. Disruption by-products can affect development, causing cognitive and endocrine issues, and structural anomalies such as corpus callosum thinning, ventriculomegaly, and hippocampal and olfactory findings. Limbic extensions may also contribute to the same structural defects as by-products. Midline CNS developmental anomalies can act as disruptive foci, most likely through vascular variants, but have separate pathogenesis. Relative frequencies of specific pituitary hormone defects change as SOD rates increase. Increasing relative rates of midline CNS developmental defects and cortical anomalies are consistent with rising levels of exogenous exposures sensitizing to midline predispositions.

Extra-pituitary midline structural abnormalities associated with ectopic posterior pituitary detected on a new rapid MRI protocol (FAST1.2).

Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

Isolated Absent Septum Pellucidum: A Retrospective Study of Fetal Diagnosis and Postnatal Outcomes.

BACKGROUND: Absent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. METHODS: This was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. RESULTS: ASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n = 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). CONCLUSIONS: Few children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal additional abnormalities that can impact prognosis and affect prenatal counseling.

Hypothesis: By-products of vascular disruption carried in the CSF affect prenatal brain development.

Prenatal CNS disruptions can be associated with physically separate findings. Examples include cognitive issues in septo-optic dysplasia and sporadic and WNT1-related unilateral cerebellar hypoplasia, and physical findings such as thinning of the corpus callosum, ventriculomegaly, hippocampal abnormalities, olfactory tract and bulb hypoplasia, and distant cortical dysplasias with schizencephaly. Similar effects to toxicities with intraventricular hemorrhage in prematurity could occur earlier in development. CSF transportation of disruption by-products would provide access to vulnerable areas through inflammatory effects on blood-brain barrier permeability. Outcomes are influenced by location and volume of byproducts in the CSF, timing, transport, and inflammatory responses. A particular association of vermis disruption with cognitive issues may be related to CSF flow distortions that avoid toxin dilutions in the third ventricle. Symmetrical contralateral cortical dysplasia with schizencephaly may reflect immunovascular field-related vulnerabilities seen in situations such as vitiligo.

Novel Genetic Diagnoses in Septo-Optic Dysplasia.

Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia.

[Septo optic dysplasia plus: about a case]. / Dysplasie septo optique plus: à propos d'un cas.

Septo optic dysplasia plus is a rare disease seen in children. Its diagnosis is radiological, based on brain magnetic resonance imaging (MRI). We report the case of a child aged 2 years and 4 months, with no particular pathological history; who consulted for psychomotor retardation, strabismus and low vision behavior. An endocrine biological assessment exploring the hypothalomo-pituitary function was carried out, revealing no abnormality. The diagnosis of septo-optic dysplasia plus was retained on the brain MRI data, in front of the agenesis of the septum pellucidum and of the splenium of the corpus callosum, the hypoplasia of the optic pathways and of the pituitary stalk as well as in front of the agenesis of the posterior pituitary. It was associated with a closed schizencephaly. Septo-optic dysplasia is a rare congenital malformation. Our objective is to recall its semiology in imaging and to underline the importance of MRI to establish the diagnosis. Septo-optic dysplasia is a rare clinical entity typically involving midline brain abnormalities, optic nerve hypoplasia, and pituitary insufficiency. The association with cortical malformations such as schizencephaly and polymicrogyria denotes the term septo-optic dysplasia plus. Advances in imaging currently allow early diagnosis, which is essential for adequate management. Antenatal ultrasound may suspect dysplasia, and brain MRI confirms the diagnosis.

Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia.

BACKGROUND: Septo-optic dysplasia (SOD) is a condition that affects the early development of the brain and eyes. It presents with a combination of optic nerve hypoplasia, brain midline structure abnormalities, and pituitary gland hypoplasia. METHODS: This is a case report of a 4-year-old male who presented with low amplitude horizontal nystagmus and decreased visual acuity 20/60 OU. Further imaging and electrophysiology were conducted to classify the ocular presentation. RESULTS: No iris transillumination was noted, but foveal hypoplasia and disc edema were evident on fundus examination. This prompted neurology consultation and MRI imaging. The MRI was consistent with the diagnosis of SOD showing hypoplasia of the optic nerves, chiasm, and tracts and an absent septum pellucidum, but with normal pituitary development and function. Lumbar puncture and intracranial pressure were normal. Genetic testing identified one pathogenic variant in the SLC45A2, indicating carrier status for oculocutaneous albinism type 4 (OCA4). Flash Visual Evoked Potentials (VEPs) were consistent with chiasm dysfunction or hypoplasia rather than the chiasmal misrouting of OCA. CONCLUSION: This case report further elaborates the phenotypic variation of SOD, with the finding of blurred disc margins, in the absence of the typical optic nerve double ring sign and with normal intracranial pressure. The findings of fovea hypoplasia and blond fundi lead to the suspicion of OCA either as a separate diagnosis with a second pathogenic variant in SCL45A2 not yet identified or in association with SOD. This case highlights the importance of electrophysiology to help distinguish chiasmal hypoplasia or dysfunction from OCA misrouting.

Septo-optic dysplasia: Ophthalmological abnormalities in a series of 5 cases.

Septo-optic dysplasia (SOD) is a rare congenital condition of unknown cause, with a characteristic triad that includes optic nerve hypoplasia, pituitary function abnormalities and midline brain defects, in addition to a broad spectrum of symptoms and associations. A total of five clinical cases are presented, four of which met the complete classic triad. All of them showed a wide variety of ophthalmological, endocrinological and neurological alterations. Within the ophthalmological spectrum of SOD, papillary hypoplasia and ocular motility alterations (nystagmus, strabismus) stand out. Other less frequent ones may also appear, such as pupillary alterations, microphthalmia and coloboma. Given the suspicion of SOD, brain MRI scan should be performed, as well as consultation with the paediatric department in order to complete the study and indicate, if necessary, systemic treatment.

Displasia septoóptica: alteraciones oftalmológicas en una serie de 5 casos / Septo-optic dysplasia: ophthalmological abnormalities in a series of 5 cases

La displasia septoóptica (DSO) es una entidad congénita, rara, de causa desconocida, con una tríada característica que incluye hipoplasia de nervio óptico, anomalías en la función hipofisaria y defectos en la línea media cerebral, además de un amplio espectro de manifestaciones y asociaciones.Se presenta una serie de cinco casos clínicos, de los cuales cuatro presentaron la tríada clásica completa. Todos mostraron gran variedad de alteraciones oftalmológicas, endocrinológicas y neurológicas.Dentro del espectro oftalmológico de la DSO, destacan la hipoplasia papilar y las alteraciones de la motilidad ocular (nistagmos estrabismo). También pueden aparecer otras menos frecuentes, como son alteraciones pupilares, microftalmia y coloboma.Ante la sospecha de DSO, conviene realizar una resonancia magnética cerebral y una interconsulta con el servicio de pediatría para completar el estudio e indicar, si fuera preciso, tratamiento sistémico.

Septo-optic dysplasia (SOD) is a rare congenital condition of unknown cause, with a characteristic triad that includes optic nerve hypoplasia, pituitary function abnormalities and midline brain defects, in addition to a broad spectrum of symptoms and associations.A total of five clinical cases are presented, four of which met the complete classic triad. All of them showed a wide variety of ophthalmological, endocrinological and neurological alterations.Within the ophthalmological spectrum of SOD, papillary hypoplasia and ocular motility alterations (nystagmus, strabismus) stand out. Other less frequent ones may also appear, such as pupillary alterations, microphthalmia and coloboma.Given the suspicion of SOD, brain MRI scan should be performed, as well as consultation with the paediatric department in order to complete the study and indicate, if necessary, systemic treatment.

A severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome with a novel description of coloboma and septo-optic dysplasia, owing to a start codon variant in the NR2F1 gene.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor subfamily 2 group F member 1) gene have been linked to this condition. A recent report has shown that pathogenic variants in the start codon lead to decreased expression of the NR2F1 protein and a relatively mild phenotype, similar to that seen in whole gene deletions, and due to the lack of the dominant negative effect. Here we describe a severe case of BBSOAS with an initiation codon missense variant. The developmental delay, seizures, optic atrophy are in keeping with features observed in this condition, however this is the first report to describe colobomas and septo-optic dysplasia as associated features potentially extending the phenotype linked to BBSOAS. In addition, this is the first description of a severe phenotype linked to a de novo missense variant in the start codon of the NR2F1 gene.

Prenatal diagnosis and outcome of fetuses with isolated agenesis of septum pellucidum: cohort study and meta-analysis.

OBJECTIVE: To evaluate the postnatal outcome of children with a prenatal diagnosis of apparently isolated agenesis of the septum pellucidum (ASP). METHODS: A retrospective cohort study of cases of prenatally diagnosed ASP followed in two tertiary centers and a meta-analysis combining data from the cohort study with data from published studies identified in a systematic review were carried out. Only cases with apparently isolated ASP on antenatal ultrasound and/or magnetic resonance imaging and with available postnatal follow-up data were considered eligible for inclusion. The following outcomes were analyzed: incidence of chromosomal anomalies, agreement between antenatal and postnatal findings, overall incidence of septo-optic dysplasia (SOD) and incidence of major neurological disability (motor, language, coordination or behavioral disorder or epilepsy) in non-SOD children. The incidence of SOD in infants with apparently normal optic pathways on antenatal imaging was also evaluated. RESULTS: Fifteen cases of isolated ASP, with median postnatal follow-up of 36 months (range, 12-60 months), were selected from the two centers. Six previously published studies met the inclusion criteria for the systematic review and a total of 78 cases were eligible for the analysis, including the 15 cases from our series. Genetic tests were carried out antenatally in 30 fetuses, of which two had an abnormal result (pooled proportion, 9.0% (95% CI, 1.8-20.7%); I2 = 0%). Additional or discordant imaging findings were noted postnatally in 9/70 (pooled proportion, 13.7% (95% CI, 3.5-29.0%); I2 = 63.9%) cases. Of all 78 neonates with available follow-up, SOD was diagnosed postnatally in 14 (pooled proportion, 19.4% (95% CI, 8.6-33.2%); I2 = 51.2%). In 60 cases, the optic pathways were considered to be normal on antenatal imaging, and six of these (pooled proportion, 9.1% (95% CI, 1.1-24.0%); I2 = 62.0%) were diagnosed postnatally with SOD. Of the 46 infants with available neurological follow-up who were not affected by SOD, a major neurological disability was diagnosed in three (pooled proportion, 6.5% (95% CI, 0.5-18.6%); I2 = 40.1%). CONCLUSIONS: In the vast majority of cases with a prenatal diagnosis of apparently isolated ASP, the prognosis is favorable. However, an additional anomaly is detected after birth in about 14% of cases and has a negative impact on clinical outcome. Detailed antenatal assessment of the brain and optic pathways is strongly recommended in order to identify the presence of associated anomalies. Antenatal visualization of apparently normal optic pathways does not rule out SOD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.